PROJECT SUMMARY/ABSTRACT Chronic liver disease affects approximately 3 million people in the United States and leads to more than 42,000 deaths each year. The overall goal of this project is to develop a protein biologic (MM-003) that acts by inhibition of galectin-3 as a therapy for prevention and treatment of chronic liver fibrosis. Fibrosis is the outcome of almost all chronic liver diseases. It is due to a dynamic scarring process caused by the response of the body to liver injury in a similar way that injury causes scarring in the skin or other organs through the deposition of collagen and other extracellular matrix (ECM) components. Fibrosis that is so extensive that the liver is no longer functional results in cirrhosis ? the main cause of death from chronic liver disease. Resolution of liver fibrosis has been shown in animal models and in patients after treatment and/or removal of a causative agent but there are no approved agents that act to prevent or reverse fibrosis. Mounting data implicate galectin-3 as a causal factor in liver fibrosis. Compared to wild type mice, galectin-3 deficient mice were protected from liver fibrosis from carbon tetrachloride exposure or bile duct ligation (BDL) despite equivalent injury. Inhibition of galectin-3 expression with small interfering (si) RNA had a therapeutic effect in the carbon tetrachloride mouse model of acute liver disease. In the BDL mouse model of chronic liver disease, galectin-3 expression was induced in hepatic stellate cells (HSCs) that give rise to the fibrogenic myofibroblasts. Systemic and hepatic vein levels of galectin-3 were increased in patients with alcoholic liver cirrhosis and the levels were negatively correlated with liver function. We postulate that inhibition of galectin-3 by MM-003 will have a preventative effect on the development of liver fibrosis, will be therapeutic for chronic liver disease, and will be safe for chronic use. The overall goal in Phase I is to obtain evidence of the potential efficacy of MM-003, a biologic inhibitor of galectin-3, for therapy of chronic liver fibrosis. There are two Specific Aims for Phase I: Aim 1. Determine the effect of MM-003 on profibrotic activity of primary human hepatic stellate cells and macrophages in vitro. Aim 2. Determine the anti-fibrotic potential of MM-003 in mouse models of liver fibrosis. 2A. Determine efficacy in preventing and treating liver fibrosis in a mouse bile duct-ligation (BDL) model of fibrosis. 2B. Determine efficacy in preventing, treating, and reversing liver fibrosis in a mouse carbon tetrachloride (CCl4) model of fibrosis.